Agents for the early treatment of ischemic stroke, within 1 to 2 hours of onset, are now available and being evaluated in clinical trials. However, there is no established diagnostic technique for identifying and localizing evolving ischemic stroke within this early time period. Recently, diffusion-weighted magnetic resonance.(MR) imaging has been used to visualize parenchymal changes in ischemic brain within one hour from vascular occlusion. This new MR modality is sensitive to the diffusion of protons in water and provides an image of the apparent diffusion constant (ADC). In ischemic regions, the intensity of the diffusion-weighted image (DWI) is increased and the ADC image is decreased. MR can also produce a brain lactate image with no lipid contamination, although with less spatial detail, by using the double quantum technique with a slotted tube resonator. The general hypothesis of this proposal is that the ischemic penumbra, that region which is salvageable in the early stages of ischemic stroke, can be identified by these new MR imaging methodologies. Our initial aim is to explore the biochemical and cellular mechanisms of the intense DWI signal in focal ischemia, using cortical superfusion and freeze lesion models to separate cerebral ischemic edema into its separate cytotoxic and vasogenic edema components. We hypothesize that the ADC is more sensitive to cytotoxic than to vasogenic edema. Our second aim will evaluate DWI for its utility in detecting and locating ischemic stroke and compare regional DWI over time to the distribution of cerebral blood flow (CBF). Specific Aim 2A will investigate the sensitivity and specificity of DWI for the detection of focal cerebral ischemia, using an embolic model of focal cerebral ischemia with inherent variability of infarct volume, in relation to different magnetic gradients and infarct volumes. Specific Aim 2B will compare MR ADC images and values to CBF determined by autoradiography in the same animal. Our goal will be to investigate the spatial and temporal fidelity of ADC for locating the ischemic region. We hypothesize that CBF and ADC will generally correlate in space or time, but the exceptions that occur will predict salvageable ischemic tissue. For this purpose, a stroke model which gives consistent volume and location will be used so that comparisons over time can be made. Our third aim will compare regional ADC and CBF to lactate, in the ischemic core and the penumbra around the core of ischemia, and during the evolution of ischemia to infarction. Lactate has a central role in the bioenergetics of ischemia. We hypothesize that lactate will not follow the time course of ADC in the penumbra and that comparing ADC and lactate will provide increased specificity for the localization of the penumbra. The question of paramount importance in ischemic stroke underlies each of these aims: Is it possible to identify salvageable ischemic tissue before it progresses to infarction? These new techniques have potential for the early evaluation of stroke and stroke therapy in humans by providing delineation of pathophysiological heterogeneity despite similar clinical symptoms in the very early hours of ischemia.